Pharmacokinetics and pharmacodynamics of ticagrelor in subjects on hemodialysis and subjects with normal renal function

Pharmacokinetics and pharmacodynamics of ticagrelor in subjects on hemodialysis and subjects with... Purpose This single-dose, randomized, open-label, parallel-group, and crossover study assessed pharmacokinetics (PK), phar- macodynamics (PD), and safety of ticagrelor in subjects on hemodialysis versus healthy subjects. Methods Hemodialysis subjects were randomized, receiving a single ticagrelor 90-mg dose 1 day post-hemodialysis or just before hemodialysis, with an intervening washout of ≥ 7 days. Healthy subjects (creatinine clearance ≥ 90 mL/min) received a single ticagrelor 90-mg dose. PK, PD (P2Y reaction units [PRU], inhibition of platelet aggregation [IPA]), and safety were evaluated. Results Twenty-seven subjects (14 hemodialysis, 13 healthy) received ticagrelor. The mean maximum plasma concentration (C ) and area under the plasma concentration curve from time zero to infinity (AUC ) of ticagrelor were 598.4 ng/mL and max 0-∞ 3256.1 ng·h/mL, respectively, in pre-hemodialysis subjects; 560.3 ng/mL and 3015.1 ng·h/mL, respectively, in post-hemodialysis subjects; and 370.8 ng/mL and 2188.8 ng·h/mL, respectively, in healthy subjects. C and AUC of AR-C124910XX, the max 0-∞ active metabolite, were 152.3 ng/mL and 1144.2 ng·h/mL, respectively, in pre-hemodialysis subjects; 130.8 ng/mL and 1127.8 ng·h/mL, respectively, in post-hemodialysis subjects; and 111.7 ng/mL and 1000.4 ng·h/mL, respectively, in healthy subjects. Mean IPA time curves over 24 h post-dose were almost indistinguishable for all three treatments. The greatest reduction in mean PRU occurred approximately 2 h post-dose for all three treatments. No safety or tolerability issues were identified. Conclusion Hemodialysis resulted in modestly higher exposure to ticagrelor and AR-C124910XX, with no clinically significant effect on PD or tolerability. Accordingly, no dose adjustment is required for hemodialysis patients. Timing of hemodialysis has little impact on ticagrelor PK, or the effect of ticagrelor on IPA. . . . Keywords Hemodialysis Pharmacokinetics Pharmacodynamics Ticagrelor Introduction (ADP)-mediated platelet aggregation [1]. It is given in com- bination with low-dose aspirin for the secondary prevention of Ticagrelor is a direct-acting, reversibly binding oral P2Y atherothrombotic events in patients with acute coronary syn- receptor antagonist that inhibits adenosine diphosphate dromes (ACS) [2–4]. Ticagrelor is primarily eliminated via hepatic metabolism, with renal excretion playing only a minor role. The primary Electronic supplementary material The online version of this article route of excretion for the active metabolite of ticagrelor is (https://doi.org/10.1007/s00228-018-2484-7) contains supplementary most probably via biliary secretion [5, 6]. The pharmacokinet- material, which is available to authorized users. ics (PK), pharmacodynamics (PD), and safety of ticagrelor have been previously studied in a variety of special popula- * Renli Teng renli.teng@careceutics.com tions, including subjects with severe renal impairment not on dialysis [7] and subjects with ACS and chronic kidney disease 1 [8]. Compared with subjects with normal renal function, the AstraZeneca, Gaithersburg, MD, USA maximum observed plasma concentration (C ) and area un- 2 max Careceutics LLC, 2016 Saint Andrews Dr, Berwyn, PA 19312, USA der the plasma concentration curve from time zero to infinity AstraZeneca, Wilmington, DE, USA (AUC of ticagrelor were 20% lower in subjects with severe 0-∞) Skyview Research, Philadelphia, PA, USA renal impairment, a difference that is not considered clinically significant. Likewise, PD measures of platelet aggregation DaVita Clinical Research, Minneapolis, MN, USA Eur J Clin Pharmacol appeared to be generally comparable in healthy subjects and < 9 g/dL; concomitant therapy with strong cytochrome those with severe renal impairment, and the safety profile was P450 3A (CYP3A) inhibitors, inducers, or substrates with a similar, with no dose adjustments required for renally im- narrow therapeutic index within 14 days of study initiation; paired subjects [7]. When assessed pharmacodynamically ver- history of alcohol, substance, or drug abuse within the year sus clopidogrel in patients with ACS and chronic kidney dis- preceding the study; and clinically significant laboratory ab- ease, ticagrelor was again shown to be effective and was as- normalities as judged by the investigator. sociated with greater reductions in P2Y platelet reaction Subjects were screened within 21 days of study initiation units (PRU) in the 24 h following loading dose [8]. (visit 1), which included a physical examination, clinical lab- The PK, PD, and safety of ticagrelor are yet to be defini- oratory testing, 12-lead electrocardiogram (ECG), and rele- tively established in subjects with end-stage renal disease vant medical and surgical history. Renal function was estimat- (ESRD) receiving renal replacement therapy with hemodialy- ed using the Cockcroft-Gault formula [12] and was used to sis. Consequently, there are no dosing recommendations for confirm group placement at screening. Laboratory assess- ticagrelor in these patients, despite their increased risk for ments were repeated prior to receiving the study drug. atherothrombotic and bleeding events when compared with Subjects with normal renal function received a single oral the general population [9–11]. ticagrelor 90-mg dose. Hemodialysis subjects received a sin- This study was conducted to determine the effects of he- gle oral ticagrelor 90-mg dose in randomized order either modialysis on the PK, PD (based on inhibition of platelet 1 day following hemodialysis (post-hemodialysis) or just prior aggregation [IPA] and platelet reactivity, reported as PRU), to the start of hemodialysis (pre-hemodialysis), with crossover safety, and tolerability of ticagrelor in subjects with ESRD to the other regimen after a washout period of at least 7 days. on hemodialysis, and to provide a rational quantitative basis All subjects were required to fast (2 h for hemodialysis for ticagrelor dosing recommendations in this patient subjects, 8 h overnight for healthy patients) prior to ticagrelor population. administration and for 2 h post-dose. Ticagrelor was adminis- tered with 120 and 240 mL of non-refrigerated water in he- modialysis and healthy subjects, respectively. Subjects sat in Methods an upright or semi-recumbent position for at least 2 h follow- ing dosing. Water consumption was restricted from 2 h prior to Study design and treatment 2 h following ticagrelor dosing. This was a single-dose, randomized, open-label, parallel- Sample collection group, and crossover study (NCT02022748) of healthy adult subjects with normal renal function and subjects on hemodi- Venous blood samples were collected at 1 (for PK only), 2, 4, alysis enrolled at two study centers (in Lakewood, Colorado 6, 12, 24, 36, and 48 h post-dose. PK samples were collected and Minneapolis, Minnesota) in the USA. The study was con- into lithium heparin tubes, chilled, and centrifuged (10 min at ducted in accordance with the ethical principles that have their 4 °C, relative force of 1500 g) within 30 min of sample col- origin in the Declaration of Helsinki and in compliance with lection. PD samples were collected in Greiner Bio-One the International Conference on Harmonisation/Good Clinical Vacuette tubes (Greiner Bio-One North America Inc., Practice guidelines, AstraZeneca bioethics policy, and other Monroe, NC, USA), allowed to set for a minimum of applicable regulatory requirements. The study protocol was 10 min, and assayed within 4 h of collection. approved by an institutional review board for each study cen- ter, and written informed consent was obtained from all PK and PD sample analyses subjects. Subjects with normal renal function (creatinine clearance Samples for determination of ticagrelor and AR-C124910XX ≥ 90 mL/min) were matched by age, weight, and sex to sub- (active metabolite) concentrations in plasma were analyzed by jects with ESRD on hemodialysis. The main inclusion criteria Covance Inc. on behalf of AstraZeneca Research and were men or women aged 18–80 years, body weight ≥ 50 kg, Development, using an appropriate bioanalytical method [13]. and body mass index (BMI) 18–40 kg/m ,with normal renal function or suffering from ESRD requiring maintenance he- PK analyses modialysis. Major exclusion criteria included pregnancy; lac- tation; indication for oral anticoagulant or antiplatelet therapy The PK parameters were estimated using standard non- during the study period (low-dose aspirin was allowed for compartmental methods and determined in the subjects who hemodialysis subjects only); history of ACS within 12 months received a dose of ticagrelor, had PK data available, and had of study start; contraindication to ticagrelor; increased no major protocol deviations that might affect the PK of bleeding risk (platelet count < 100,000/μL) or hemoglobin ticagrelor or AR-C124910XX. The following PK parameters Eur J Clin Pharmacol were estimated for ticagrelor and AR-C124910XX: C , Comparisons of the two hemodialysis regimens were per- max AUC , time to reach maximum plasma concentration (t ), formed using a mixed model. Descriptive analyses were per- 0-∞ max terminal elimination half-life (t ), and metabolite/parent drug formed for each PD parameter, but the study was not powered 1/2 C and AUC ratios. PK parameters were estimated using for statistical analysis of PD. Sample size determinations were max WinNonlin version 6.3 (Pharsight Corporation, Mountain based on accepted standards for this type of investigation. View, CA, USA). PD analyses Results The PD profile of ticagrelor was determined in the subjects Demographics and disposition who received a dose of ticagrelor, had PD data available, and had no major protocol deviations that might affect evaluation Twenty-seven subjects (14 hemodialysis subjects, 13 healthy of PD, and was based on IPA and platelet reactivity. IPA was subjects) received the study drug and underwent study proce- measured by light transmission aggregometry using 20-μM dures between October 2015 and May 2016. Three hemodial- ADP as the agonist [14]. The peak IPA (IPA ) was estimat- ysis subjects discontinued treatment (two who received the max ed as the highest IPA (final extent); time to IPA was also pre-hemodialysis regimen first and one who received the max assessed. The area under the effect curves from 0 to 48 h of post-hemodialysis regimen first). In two subjects, discontinu- final extent IPA (AUEC ) were calculated from IPA ations were due to AEs, while the third subject chose to dis- 0–48, IPA time curves using the linear trapezoid rule. IPA percentage continue the study after receiving the first ticagrelor dose. All was calculated at each time point using the following formula: 13 healthy subjects completed treatment. 100 × (PA − PA )/PA ,where PA is the mean platelet ag- Healthy and hemodialysis subjects were generally well BL T BL T gregation response at time T,andPA is the mean response at matched. The hemodialysis group comprised 12 men and 2 BL pre-dose on day 1. The relationship between ticagrelor plasma women, and had a mean (standard deviation [SD]) age of concentrations and IPAwas investigated using a sigmoid max- 50.6 (12.5) years and a mean (SD) BMI of 27.8 (4.2) kg/m . γ γ γ imum effect (E )model:IPA = E C /(C +EC ), where The healthy subject group comprised 10 men and 3 women, max max 50 E is the maximum effect, EC is the concentration that with a mean (SD) age and BMI of 43.8 (10.4) years and max 50 produces 50% of maximal effect, gamma (γ)isthe 28.3 (3.8) kg/m , respectively. In the hemodialysis group, five sigmoidicity or shape factor, and C is the plasma concentra- subjects were white and nine were black. Of the healthy sub- tion of ticagrelor. jects, six were white, five were black, and two were of other Platelet reactivity was measured with the VerifyNow™ race. P2Y assay (Accriva Diagnostics, San Diego, CA, USA), All hemodialysis subjects were on concomitant medica- with results reported in PRU. The minimum PRU value tion, including treatments for hyperparathyroidism (PRU ) was estimated as the lowest PRU value. The area (doxercalciferol) and anemia (saccharated iron oxide, min under the effect curves from 0 to 48 h of final PRU (AUEC erythropoiesis-stimulating agents), and anticoagulants (hepa- 0– ) were calculated from PRU time curves using the linear rin). One hemodialysis subject had taken amlodipine within 48, PRU trapezoid rule. 14 days of study initiation, and although this was recorded as a protocol deviation, it was considered to have negligible im- Safety and tolerability pact on the PK of ticagrelor and the subject was included in the PK analysis population. Two healthy subjects reported Assessments of safety and tolerability were based on the safe- taking concomitant medications, which included acetamino- ty population (comprising all patients who received a dose of phen, antacids (calcium carbonate), and aspirin. ticagrelor) and included monitoring of adverse events (AEs), physical examination, 12-lead ECGs, vital signs, and labora- Pharmacokinetics tory testing. AEs were monitored from time of informed con- sent until follow-up. The mean concentration–time profiles of ticagrelor and AR-C124910XX were comparable in hemodialysis and Statistical analyses healthy subjects (Fig. 1), and the timing of ticagrelor dos- ing relative to hemodialysis did not appear to impact the PK parameters were summarized using descriptive statistics. plasma concentration profile. All other analyses were generated using SAS® version 9.3 Ticagrelor was rapidly absorbed, with a median t of 2 h max (SAS Institute, Inc., Cary, NC, USA). Treatment comparisons in both hemodialysis and healthy subjects, and the mean t 1/2 between healthy and hemodialysis subjects were performed was comparable for all treatments (Table 1). The mean C of max using general linear methods with treatment effects. ticagrelor was 61% higher in subjects receiving the pre- Eur J Clin Pharmacol Fig. 1 Mean (SD) of plasma concentration time curves for a ticagrelor and b AR-C124910XX for hemodialysis and healthy subjects. HD hemodialysis, SD standard deviation hemodialysis ticagrelor treatment, compared with that in treatment was 17% higher versus that in healthy subjects. healthy subjects, and 51% higher following the post- The mean AUC of AR-C124910XX was 14 and 13% 0-∞ hemodialysis regimen than that in healthy subjects (Table 1, higher in subjects receiving ticagrelor pre- and post-hemodi- Table S1). Likewise, the mean AUC of ticagrelor was 49 alysis, respectively, than that in healthy subjects (Table 1, 0-∞ and 38% higher when ticagrelor was given pre- and post- Table S1), and like ticagrelor itself, exposure to hemodialysis, respectively, than that in healthy subjects AR-C124910XX was similar for the two hemodialysis (Table 1, Table S1). The mean C and AUC of ticagrelor treatment schedules. C of AR-C124910XX values max 0-∞ max were comparable for the two hemodialysis treatments (Table displayed minor variability between the two hemodialysis 1). The variability (CV%) for both C and AUC of ticag- regimens (pre-hemodialysis, 54%; post-hemodialysis, 38%). max 0-∞ relor was approximately 50% in hemodialysis subjects, com- The variability of AUC of AR-C124910XX was approx- 0-∞ pared with 37% for C and 23% for AUC in healthy subjects. imately 40% for both hemodialysis treatment schedules. The max 0-∞ AR-C124910XX was rapidly formed, with a median t variability of C and AUC of AR-C124910XX was 60 max max 0-∞ of 2 h in both hemodialysis and healthy subjects, and the and 33%, respectively, for healthy subjects. The variability mean t was similar for all treatments (Table 1). In addi- of C and AUC of AR-C124910XX was considered to 1/2 max 0-∞ tion, the mean C of AR-C124910XX was 36% higher be generally similar for hemodialysis versus healthy max following the pre-hemodialysis regimen, compared with that subjects. in healthy subjects (Table 1, Table S1). The mean C of The mean metabolite-to-parent ratios for C (range, max max AR-C124910XX in patients receiving post-hemodialysis 0.26–0.33) and AUC (range, 0.38–0.50) were also 0-∞ Table 1 Pharmacokinetic (PK) PK parameter Pre-HD (n = 13) Post-HD (n = 12) Healthy subjects (n =13) parameters for ticagrelor and ARC-124910XX in hemodialysis Ticagrelor and healthy subjects C , ng/mL 598.4 (47.9) 560.3 (54.0) 370.8 (37.3) max AUC , ng·h/mL 3256.1 (52.5) 3015.1 (54.2) 2188.8 (22.6) 0-∞ t , h 2.0 (1.0–4.0) 2.0 (1.0–4.0) 2.0 (1.0–6.0) max t , h 8.4 (24.8) 8.2 (16.2) 8.3 (14.9) 1/2 AR-C124910XX C , ng/mL 152.3 (54.3) 130.8 (38.3) 111.7 (60.0) max AUC , ng·h/mL 1144.2 (36.2) 1127.8 (39.3) 1000.4 (33.2) 0-∞ t , h 2.0 (2.0–4.0) 2.0 (2.0–4.0) 2.0 (2.0–6.0) max t , h 7.4 (24.8) 7.3 (28.2) 8.4 (22.3) 1/2 AUC , area under the concentration curve (AUC) from time zero to infinity; C , maximum observed plasma 0-∞ max concentration; HD, hemodialysis; t , terminal elimination half-life; t , time to reach maximum plasma 1/2 max concentration Values are geometric mean (percentage coefficient of variation) for C ,AUC ; median (range) for t ; max 0-∞ max arithmetic mean (standard deviation) for t 1/2 Eur J Clin Pharmacol generally similar between hemodialysis and healthy subjects, approximately 2 h post-dose for all three treatments (Fig. 4). suggesting that the presence of ESRD requiring hemodialysis The PRU responses (both absolute values and changes from and the timing of hemodialysis have little influence on the the baseline) were similar following ticagrelor pre- and post- metabolic conversion of ticagrelor to AR-C124910XX. hemodialysis, while there were much greater responses (lower absolute PRU values) observed in the healthy subjects com- pared with the hemodialysis subjects (Table 2). The PRU dif- Pharmacodynamics ferences at baseline between hemodialysis subjects and healthy subjects contributed to the PRU difference observed The mean IPA time curves over 24 h post-dose were almost at early time points after ticagrelor dosing. Additionally, the indistinguishable for all three treatments (Fig. 2). Moreover, difference in effect of ticagrelor on PRU measured as the final extent IPA was over 90% for all three treatments approx- absolute PRU changes from their baselines is less pronounced imately2hafter ticagrelor administration(Fig. 2). The mean which indicates that hemodialysis subjects did not have a IPA and the AUEC were generally similar for all greater PRU response when compared with healthy subjects. max 0–48, IPA three treatments (Table 2), indicating that the presence of ESRD on hemodialysis and the timing of hemodialysis have Safety little influence on the effect of ticagrelor on IPA. The median time to IPA was longer when ticagrelor was administered AEs were reported in seven individuals during the study treat- max just prior to hemodialysis (4 h) than 1 day after hemodialysis ment period, distributed across all three treatments (five he- (2 h) or in healthy subjects (2 h) (Table 2). Time to IPA modialysis subjects [three when ticagrelor was administered max displayed much greater variability in hemodialysis subjects pre-hemodialysis and two when ticagrelor was administered (range 2–12 h for both treatments) than in healthy subjects post-hemodialysis] and two healthy subjects). There were no (2 h in all 13 subjects) (Table 2). The E model parameters reports of bleeding or dyspnea in hemodialysis or healthy max describing the PK/PD relationship between plasma concentra- subjects who received ticagrelor. One subject who received tions of ticagrelor and IPA were comparable across all three ticagrelor post-hemodialysis reported potentially treatment- treatments (Fig. 3), suggesting that the relationship between related AEs according to the investigator, comprising dizzi- ticagrelor concentrations and IPA is not altered in ESRD pa- ness, bronchospasm, and nausea. This patient withdrew from tients on hemodialysis (Table 2). the study before receiving the second ticagrelor dose. One The mean PRU was decreased following ticagrelor dosing, other hemodialysis subject withdrew from the study because with the greatest change from baseline occurring of a serious AE (thoracic vertebral fracture), which was not considered treatment related. There were no other serious AEs or deaths, and no clinically significant changes in laboratory parameters or vital signs were reported during the study. Discussion This study investigated the PK, PD, and safety of ticagrelor in subjects with ESRD on hemodialysis and compared the results with those from healthy subjects with normal renal function. The effects of timing of hemodialysis on the PK of ticagrelor were also investigated as part of the study. Overall, hemodialysis did not have a clinically significant impact on the exposure to ticagrelor or its active metabolite. The mean C and AUC of ticagrelor were 61 and 51%, max 0-∞ and 49 and 38% higher in pre- and post-hemodialysis subjects than in healthy subjects, respectively, while the mean C max and AUC of AR-C124910XX were 36 and 17%, and 14 0-∞ and 13% higher in pre- and post-hemodialysis subjects, re- spectively, than that in healthy subjects. Notably, the mean C and AUC of ticagrelor and AR-C124910XX were max 0-∞ generally similar following a single 90-mg dose of ticagrelor Fig. 2 Mean (SD) inhibition of platelet aggregation (IPA) time curves for 1 day after hemodialysis and 2 days prior to the next dialysis ticagrelor in hemodialysis and healthy subjects. HD hemodialysis, SD standard deviation treatment, indicating that timing of hemodialysis has little Eur J Clin Pharmacol Table 2 Pharmacodynamic (PD) PD parameter Pre-HD (n = 13) Post-HD (n = 12) Healthy subjects (n =13) parameters for ticagrelor in hemodialysis and healthy subjects IPA , % 92.8 (9.3) 95.5 (7.6) 95.9 (5.3) max TIPA , h 4.0 (2.0–12.0) 2.0 (2.0–12.0) 2.0 (2.0–2.0) max AUEC , %·h 2576.4 (32.1) 2550.3 (27.3) 2472.4 (46.0) 0–48, IPA E , % 92.1 (4.3) 105.3 (10.4) 101.3 (10.4) max EC , ng/mL 9.0 (1.4) 15.5 (6.4) 8.4 (3.4) Gamma 1.1 (0.2) 0.7 (0.1) 0.7 (0.2) PRU , PRU 83.8 (115.3) 33.4 (265.3) 7.3 (170.9) min TPRU , h 2.0 (2.0–12.0) 2.0 (2.0–4.0) 2.0 (2.0–6.0) min AUEC , PRU·h 12,440.0 (26.2) 12,577.2 (30.5) 7144.9 (42.9) 0–48, PRU AUEC area under the effect curve 0 to 48 h inhibition of platelet aggregation; AUEC area under 0–48, IPA, 0–48, PRU, the effect curve 0 to 48 h P2Y reaction units; EC , concentration that produces 50% maximum effect; E , 12 50 max maximum effect; Gamma, sigmoidicity or shape factor; HD, hemodialysis; IPA , maximum inhibition of max platelet aggregation; PRU , minimum P2Y reaction units; TIPA ,timeto IPA ; TPRU ,time toPRU min 12 max max min min Values are geometric mean (percentage coefficient of variation) for IPA , AUEC , PRU , and max 0–48, IPA min AUEC ; median (range) for TIPA and TPRU ; estimate (standard error) for E ,EC , and gamma 0–48, PRU max min max 50 effect on exposure to the drug or its metabolite. Moreover, the were almost indistinguishable, and final extent IPAwas > 90% mean metabolite-to-parent C and AUC ratios were com- at 2 h post-dose in both hemodialysis and healthy subjects. max 0-∞ parable following all three treatments, suggesting that hemo- Likewise, mean IPA and AUEC were similar across max 0–48, IPA dialysis has little impact on the metabolic conversion of the three treatments. Median time to IPA was slightly lon- max ticagrelor to AR-C124910XX. ger when ticagrelor was administered just prior to hemodial- The minimal impact of hemodialysis on ticagrelor PK ob- ysis versus 1 day after hemodialysis or in healthy subjects. served in this study is consistent with the known elimination However, time to IPA values in hemodialysis subjects max pathway of ticagrelor, which is predominantly via hepatic me- displayed greater variability than those for healthy subjects, tabolism of ticagrelor to AR-C1249XX, followed by biliary possibly reflecting the small sample size. Nevertheless, the secretion [5, 6]. Renal excretion plays only a minor role in the E model parameters describing the PK/PD relationship be- max elimination of ticagrelor [5]. Moreover, as ticagrelor is highly tween ticagrelor concentrations and IPA response were com- protein bound (> 99.8%) [15], dialysis is unlikely to have an parable across all three treatments. Of particular note, these appreciable impact on its plasma concentration. The results of findings show that hemodialysis subjects did not have greater this study are also consistent with findings from subjects with responses to ticagrelor than healthy subjects, and that the severe renal impairment not on hemodialysis, which demon- timing of hemodialysis has little influence on the PD effect strated exposure to ticagrelor and AR-C124910XX (20% low- of ticagrelor on IPA. er and 17% higher, respectively, vs healthy subjects) to be For all three treatments, reductions in PRU were observed largely unaffected by renal impairment [7]. following ticagrelor dosing, with the greatest reductions ob- IPA responses were also similar between hemodialysis and served at 2 h post-dose. The mean AUEC was of 0–48, PRU healthy subjects. Mean IPA time curves for all three treatments similar magnitude when ticagrelor was administered pre- or Fig. 3 Inhibition of platelet aggregation (IPA) concentration curves for ticagrelor in hemodialysis and healthy subjects. HD hemodialysis Eur J Clin Pharmacol Administration-approved label for ticagrelor, which suggests that even a twofold increase in exposure to ticagrelor does not warrant a dose adjustment [17]. Furthermore, the timing of hemodialysis has little effect on the PK and PD of ticagrelor. Contributions of Authors R. Teng was involved in developing the study concept and design, interpreting the data, and developing the man- uscript. S. Muldowney contributed to the study concept and design, in- terpretation of data, and development of the manuscript. Y. Zhao was involved in developing the study concept and design, interpreting the data, and developing the manuscript. J.K. Berg was involved in develop- ing the study concept and design, performing study research, interpreting the data, and developing the manuscript. J. Lu contributed to the study concept and design, interpretation of the data, and development of the manuscript. N.D. Khan was involved in developing the study concept and design, interpreting the data, and developing the manuscript. Funding This study was funded by AstraZeneca. Compliance with ethical standards Conflict of interest S. Muldowney and N.D. Khan are employees and shareholders of AstraZeneca. Y. Zhao is a former consultant to Fig. 4 Mean (SD) P2Y reaction unit (PRU) time curves for ticagrelor in 12 AstraZeneca. R. Teng and J. Lu are former employees of AstraZeneca. hemodialysis and healthy subjects. HD hemodialysis, SD standard J. Berg is an employee of DaVita Clinical Research and a principal in- deviation vestigator in the trial. Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institu- post-hemodialysis. However, there appeared to be a greater tional and/or national research committee and with the 1964 Helsinki reduction in PRU in healthy subjects. This finding may be at declaration and its later amendments or comparable ethical standards. least partially explained by baseline differences in PRU in hemodialysis versus healthy subjects that may have contribut- Informed consent Informed consent was obtained from all individual ed to the PRU difference observed at early time points after participants included in the study. ticagrelor dosing. Importantly, from a safety perspective in Open Access This article is distributed under the terms of the Creative this special population, this study highlights that hemodialysis Commons Attribution 4.0 International License (http:// subjects showed no greater PRU response, compared with creativecommons.org/licenses/by/4.0/), which permits unrestricted use, healthy subjects. distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link In this single-dose study, safety data were in line with pre- to the Creative Commons license, and indicate if changes were made. vious studies of ticagrelor in healthy volunteers [16] and sub- jects with severe renal impairment not on dialysis [7]. AEs were reported in seven subjects across all treatment regi- References mens—three subjects receiving ticagrelor pre-hemodialysis, two subjects receiving ticagrelor post-hemodialysis, and two 1. Nawarskas JJ, Snowden SS (2011) Critical appraisal of ticagrelor in healthy subjects. Similarly, vital signs and laboratory findings the management of acute coronary syndrome. Ther Clin Risk following ticagrelor administration were unremarkable in he- Manag 7:473–488 modialysis and healthy subjects, again consistent with previ- 2. O’Gara PT, Kushner FG, Ascheim DD et al (2013) 2013 ACCF/ ously reported findings in healthy [16] and renally impaired AHA guideline for the management of ST-elevation myocardial subjects [7]. infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice In conclusion, the slightly higher exposure to ticagrelor and Guidelines. J Am Coll Cardiol 61:e78–e140 its active metabolite in hemodialysis subjects, compared with 3. Steg PG, James SK, Atar D et al (2012) ESC guidelines for the healthy subjects, is considered of minimal clinical relevance. management of acute myocardial infarction in patients presenting Hemodialysis subjects had similar IPA response and no great- with ST-segment elevation. Eur Heart J 33:2569–2619 er PRU response versus healthy subjects, and the safety profile 4. Roffi M, Patrono C, Collet JP et al (2016) 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting was similar in both cohorts. Based on the PK, PD, and safety without persistent ST-segment elevation: task Force for the findings of this study, no ticagrelor dose adjustment is re- Management of Acute Coronary Syndromes in Patients quired for patients with ESRD on hemodialysis. These find- Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 37:267–315 ings are consistent with the US Food and Drug Eur J Clin Pharmacol 5. Teng R, Oliver S, Hayes MA, Butler K (2010) Absorption, distri- update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 80:572–586 bution, metabolism, and excretion of ticagrelor in healthy subjects. Drug Metab Dispos 38:1514–1521 12. Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance 6. Teng R (2015) Ticagrelor: pharmacokinetic, pharmacodynamic from serum creatinine. Nephron 16:31–41 and pharmacogenetic profile: an update. Clin Pharmacokinet 13. Sillen H, Cook M, Davis P (2010) Determination of ticagrelor and 54:1125–1138 two metabolites in plasma samples by liquid chromatography and 7. Butler K, Teng R (2012) Pharmacokinetics, pharmacodynamics, mass spectrometry. J Chromatogr B Analyt Technol Biomed Life and safety of ticagrelor in volunteers with severe renal impairment. Sci 878:2299–2306 J Clin Pharmacol 52:1388–1398 14. Butler K, Teng R (2010) Pharmacokinetics, pharmacodynamics, 8. Wang H, Qi J, Li Y et al (2017) Pharmacodynamics and pharma- safety and tolerability of multiple ascending doses of ticagrelor in cokinetics of ticagrelor vs. clopidogrel in patients with acute coro- healthy volunteers. Br J Clin Pharmacol 70:65–77 nary syndromes and chronic kidney disease. Br J Clin Pharmacol 15. Butler K, Teng R (2011) Pharmacokinetics, pharmacodynamics, 84:88–96 and safety of ticagrelor in volunteers with mild hepatic impairment. 9. USRDS United States Renal Data System (2016) USRDS Annual J Clin Pharmacol 51:978–987 Data Report|Volume 2 ESRD in the United States. Chapter 9: 16. Teng R, Butler K (2010) Pharmacokinetics, pharmacodynamics, Cardiovascular disease in patients with ESRD. 2.9:465–480 tolerability and safety of single ascending doses of ticagrelor, a 10. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY (2004) reversibly binding oral P2Y(12) receptor antagonist, in healthy sub- Chronic kidney disease and the risks of death, cardiovascular jects. Eur J Clin Pharmacol 66:487–496 events, and hospitalization. N Engl J Med 351:1296–1305 17. AstraZeneca (2016) BRILINTA highlights of prescribing informa- 11. Herzog CA, Asinger RW, Berger AK et al (2011) tion. BRILINTA (ticagrelor) tablets for oral use:1-10, available at: Cardiovascular disease in chronic kidney disease. A clinical https://www.azpicentral.com/brilinta/brilinta.pdf http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Clinical Pharmacology Springer Journals

Pharmacokinetics and pharmacodynamics of ticagrelor in subjects on hemodialysis and subjects with normal renal function

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Springer Berlin Heidelberg
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Copyright © 2018 by The Author(s)
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Biomedicine; Pharmacology/Toxicology
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0031-6970
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10.1007/s00228-018-2484-7
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Abstract

Purpose This single-dose, randomized, open-label, parallel-group, and crossover study assessed pharmacokinetics (PK), phar- macodynamics (PD), and safety of ticagrelor in subjects on hemodialysis versus healthy subjects. Methods Hemodialysis subjects were randomized, receiving a single ticagrelor 90-mg dose 1 day post-hemodialysis or just before hemodialysis, with an intervening washout of ≥ 7 days. Healthy subjects (creatinine clearance ≥ 90 mL/min) received a single ticagrelor 90-mg dose. PK, PD (P2Y reaction units [PRU], inhibition of platelet aggregation [IPA]), and safety were evaluated. Results Twenty-seven subjects (14 hemodialysis, 13 healthy) received ticagrelor. The mean maximum plasma concentration (C ) and area under the plasma concentration curve from time zero to infinity (AUC ) of ticagrelor were 598.4 ng/mL and max 0-∞ 3256.1 ng·h/mL, respectively, in pre-hemodialysis subjects; 560.3 ng/mL and 3015.1 ng·h/mL, respectively, in post-hemodialysis subjects; and 370.8 ng/mL and 2188.8 ng·h/mL, respectively, in healthy subjects. C and AUC of AR-C124910XX, the max 0-∞ active metabolite, were 152.3 ng/mL and 1144.2 ng·h/mL, respectively, in pre-hemodialysis subjects; 130.8 ng/mL and 1127.8 ng·h/mL, respectively, in post-hemodialysis subjects; and 111.7 ng/mL and 1000.4 ng·h/mL, respectively, in healthy subjects. Mean IPA time curves over 24 h post-dose were almost indistinguishable for all three treatments. The greatest reduction in mean PRU occurred approximately 2 h post-dose for all three treatments. No safety or tolerability issues were identified. Conclusion Hemodialysis resulted in modestly higher exposure to ticagrelor and AR-C124910XX, with no clinically significant effect on PD or tolerability. Accordingly, no dose adjustment is required for hemodialysis patients. Timing of hemodialysis has little impact on ticagrelor PK, or the effect of ticagrelor on IPA. . . . Keywords Hemodialysis Pharmacokinetics Pharmacodynamics Ticagrelor Introduction (ADP)-mediated platelet aggregation [1]. It is given in com- bination with low-dose aspirin for the secondary prevention of Ticagrelor is a direct-acting, reversibly binding oral P2Y atherothrombotic events in patients with acute coronary syn- receptor antagonist that inhibits adenosine diphosphate dromes (ACS) [2–4]. Ticagrelor is primarily eliminated via hepatic metabolism, with renal excretion playing only a minor role. The primary Electronic supplementary material The online version of this article route of excretion for the active metabolite of ticagrelor is (https://doi.org/10.1007/s00228-018-2484-7) contains supplementary most probably via biliary secretion [5, 6]. The pharmacokinet- material, which is available to authorized users. ics (PK), pharmacodynamics (PD), and safety of ticagrelor have been previously studied in a variety of special popula- * Renli Teng renli.teng@careceutics.com tions, including subjects with severe renal impairment not on dialysis [7] and subjects with ACS and chronic kidney disease 1 [8]. Compared with subjects with normal renal function, the AstraZeneca, Gaithersburg, MD, USA maximum observed plasma concentration (C ) and area un- 2 max Careceutics LLC, 2016 Saint Andrews Dr, Berwyn, PA 19312, USA der the plasma concentration curve from time zero to infinity AstraZeneca, Wilmington, DE, USA (AUC of ticagrelor were 20% lower in subjects with severe 0-∞) Skyview Research, Philadelphia, PA, USA renal impairment, a difference that is not considered clinically significant. Likewise, PD measures of platelet aggregation DaVita Clinical Research, Minneapolis, MN, USA Eur J Clin Pharmacol appeared to be generally comparable in healthy subjects and < 9 g/dL; concomitant therapy with strong cytochrome those with severe renal impairment, and the safety profile was P450 3A (CYP3A) inhibitors, inducers, or substrates with a similar, with no dose adjustments required for renally im- narrow therapeutic index within 14 days of study initiation; paired subjects [7]. When assessed pharmacodynamically ver- history of alcohol, substance, or drug abuse within the year sus clopidogrel in patients with ACS and chronic kidney dis- preceding the study; and clinically significant laboratory ab- ease, ticagrelor was again shown to be effective and was as- normalities as judged by the investigator. sociated with greater reductions in P2Y platelet reaction Subjects were screened within 21 days of study initiation units (PRU) in the 24 h following loading dose [8]. (visit 1), which included a physical examination, clinical lab- The PK, PD, and safety of ticagrelor are yet to be defini- oratory testing, 12-lead electrocardiogram (ECG), and rele- tively established in subjects with end-stage renal disease vant medical and surgical history. Renal function was estimat- (ESRD) receiving renal replacement therapy with hemodialy- ed using the Cockcroft-Gault formula [12] and was used to sis. Consequently, there are no dosing recommendations for confirm group placement at screening. Laboratory assess- ticagrelor in these patients, despite their increased risk for ments were repeated prior to receiving the study drug. atherothrombotic and bleeding events when compared with Subjects with normal renal function received a single oral the general population [9–11]. ticagrelor 90-mg dose. Hemodialysis subjects received a sin- This study was conducted to determine the effects of he- gle oral ticagrelor 90-mg dose in randomized order either modialysis on the PK, PD (based on inhibition of platelet 1 day following hemodialysis (post-hemodialysis) or just prior aggregation [IPA] and platelet reactivity, reported as PRU), to the start of hemodialysis (pre-hemodialysis), with crossover safety, and tolerability of ticagrelor in subjects with ESRD to the other regimen after a washout period of at least 7 days. on hemodialysis, and to provide a rational quantitative basis All subjects were required to fast (2 h for hemodialysis for ticagrelor dosing recommendations in this patient subjects, 8 h overnight for healthy patients) prior to ticagrelor population. administration and for 2 h post-dose. Ticagrelor was adminis- tered with 120 and 240 mL of non-refrigerated water in he- modialysis and healthy subjects, respectively. Subjects sat in Methods an upright or semi-recumbent position for at least 2 h follow- ing dosing. Water consumption was restricted from 2 h prior to Study design and treatment 2 h following ticagrelor dosing. This was a single-dose, randomized, open-label, parallel- Sample collection group, and crossover study (NCT02022748) of healthy adult subjects with normal renal function and subjects on hemodi- Venous blood samples were collected at 1 (for PK only), 2, 4, alysis enrolled at two study centers (in Lakewood, Colorado 6, 12, 24, 36, and 48 h post-dose. PK samples were collected and Minneapolis, Minnesota) in the USA. The study was con- into lithium heparin tubes, chilled, and centrifuged (10 min at ducted in accordance with the ethical principles that have their 4 °C, relative force of 1500 g) within 30 min of sample col- origin in the Declaration of Helsinki and in compliance with lection. PD samples were collected in Greiner Bio-One the International Conference on Harmonisation/Good Clinical Vacuette tubes (Greiner Bio-One North America Inc., Practice guidelines, AstraZeneca bioethics policy, and other Monroe, NC, USA), allowed to set for a minimum of applicable regulatory requirements. The study protocol was 10 min, and assayed within 4 h of collection. approved by an institutional review board for each study cen- ter, and written informed consent was obtained from all PK and PD sample analyses subjects. Subjects with normal renal function (creatinine clearance Samples for determination of ticagrelor and AR-C124910XX ≥ 90 mL/min) were matched by age, weight, and sex to sub- (active metabolite) concentrations in plasma were analyzed by jects with ESRD on hemodialysis. The main inclusion criteria Covance Inc. on behalf of AstraZeneca Research and were men or women aged 18–80 years, body weight ≥ 50 kg, Development, using an appropriate bioanalytical method [13]. and body mass index (BMI) 18–40 kg/m ,with normal renal function or suffering from ESRD requiring maintenance he- PK analyses modialysis. Major exclusion criteria included pregnancy; lac- tation; indication for oral anticoagulant or antiplatelet therapy The PK parameters were estimated using standard non- during the study period (low-dose aspirin was allowed for compartmental methods and determined in the subjects who hemodialysis subjects only); history of ACS within 12 months received a dose of ticagrelor, had PK data available, and had of study start; contraindication to ticagrelor; increased no major protocol deviations that might affect the PK of bleeding risk (platelet count < 100,000/μL) or hemoglobin ticagrelor or AR-C124910XX. The following PK parameters Eur J Clin Pharmacol were estimated for ticagrelor and AR-C124910XX: C , Comparisons of the two hemodialysis regimens were per- max AUC , time to reach maximum plasma concentration (t ), formed using a mixed model. Descriptive analyses were per- 0-∞ max terminal elimination half-life (t ), and metabolite/parent drug formed for each PD parameter, but the study was not powered 1/2 C and AUC ratios. PK parameters were estimated using for statistical analysis of PD. Sample size determinations were max WinNonlin version 6.3 (Pharsight Corporation, Mountain based on accepted standards for this type of investigation. View, CA, USA). PD analyses Results The PD profile of ticagrelor was determined in the subjects Demographics and disposition who received a dose of ticagrelor, had PD data available, and had no major protocol deviations that might affect evaluation Twenty-seven subjects (14 hemodialysis subjects, 13 healthy of PD, and was based on IPA and platelet reactivity. IPA was subjects) received the study drug and underwent study proce- measured by light transmission aggregometry using 20-μM dures between October 2015 and May 2016. Three hemodial- ADP as the agonist [14]. The peak IPA (IPA ) was estimat- ysis subjects discontinued treatment (two who received the max ed as the highest IPA (final extent); time to IPA was also pre-hemodialysis regimen first and one who received the max assessed. The area under the effect curves from 0 to 48 h of post-hemodialysis regimen first). In two subjects, discontinu- final extent IPA (AUEC ) were calculated from IPA ations were due to AEs, while the third subject chose to dis- 0–48, IPA time curves using the linear trapezoid rule. IPA percentage continue the study after receiving the first ticagrelor dose. All was calculated at each time point using the following formula: 13 healthy subjects completed treatment. 100 × (PA − PA )/PA ,where PA is the mean platelet ag- Healthy and hemodialysis subjects were generally well BL T BL T gregation response at time T,andPA is the mean response at matched. The hemodialysis group comprised 12 men and 2 BL pre-dose on day 1. The relationship between ticagrelor plasma women, and had a mean (standard deviation [SD]) age of concentrations and IPAwas investigated using a sigmoid max- 50.6 (12.5) years and a mean (SD) BMI of 27.8 (4.2) kg/m . γ γ γ imum effect (E )model:IPA = E C /(C +EC ), where The healthy subject group comprised 10 men and 3 women, max max 50 E is the maximum effect, EC is the concentration that with a mean (SD) age and BMI of 43.8 (10.4) years and max 50 produces 50% of maximal effect, gamma (γ)isthe 28.3 (3.8) kg/m , respectively. In the hemodialysis group, five sigmoidicity or shape factor, and C is the plasma concentra- subjects were white and nine were black. Of the healthy sub- tion of ticagrelor. jects, six were white, five were black, and two were of other Platelet reactivity was measured with the VerifyNow™ race. P2Y assay (Accriva Diagnostics, San Diego, CA, USA), All hemodialysis subjects were on concomitant medica- with results reported in PRU. The minimum PRU value tion, including treatments for hyperparathyroidism (PRU ) was estimated as the lowest PRU value. The area (doxercalciferol) and anemia (saccharated iron oxide, min under the effect curves from 0 to 48 h of final PRU (AUEC erythropoiesis-stimulating agents), and anticoagulants (hepa- 0– ) were calculated from PRU time curves using the linear rin). One hemodialysis subject had taken amlodipine within 48, PRU trapezoid rule. 14 days of study initiation, and although this was recorded as a protocol deviation, it was considered to have negligible im- Safety and tolerability pact on the PK of ticagrelor and the subject was included in the PK analysis population. Two healthy subjects reported Assessments of safety and tolerability were based on the safe- taking concomitant medications, which included acetamino- ty population (comprising all patients who received a dose of phen, antacids (calcium carbonate), and aspirin. ticagrelor) and included monitoring of adverse events (AEs), physical examination, 12-lead ECGs, vital signs, and labora- Pharmacokinetics tory testing. AEs were monitored from time of informed con- sent until follow-up. The mean concentration–time profiles of ticagrelor and AR-C124910XX were comparable in hemodialysis and Statistical analyses healthy subjects (Fig. 1), and the timing of ticagrelor dos- ing relative to hemodialysis did not appear to impact the PK parameters were summarized using descriptive statistics. plasma concentration profile. All other analyses were generated using SAS® version 9.3 Ticagrelor was rapidly absorbed, with a median t of 2 h max (SAS Institute, Inc., Cary, NC, USA). Treatment comparisons in both hemodialysis and healthy subjects, and the mean t 1/2 between healthy and hemodialysis subjects were performed was comparable for all treatments (Table 1). The mean C of max using general linear methods with treatment effects. ticagrelor was 61% higher in subjects receiving the pre- Eur J Clin Pharmacol Fig. 1 Mean (SD) of plasma concentration time curves for a ticagrelor and b AR-C124910XX for hemodialysis and healthy subjects. HD hemodialysis, SD standard deviation hemodialysis ticagrelor treatment, compared with that in treatment was 17% higher versus that in healthy subjects. healthy subjects, and 51% higher following the post- The mean AUC of AR-C124910XX was 14 and 13% 0-∞ hemodialysis regimen than that in healthy subjects (Table 1, higher in subjects receiving ticagrelor pre- and post-hemodi- Table S1). Likewise, the mean AUC of ticagrelor was 49 alysis, respectively, than that in healthy subjects (Table 1, 0-∞ and 38% higher when ticagrelor was given pre- and post- Table S1), and like ticagrelor itself, exposure to hemodialysis, respectively, than that in healthy subjects AR-C124910XX was similar for the two hemodialysis (Table 1, Table S1). The mean C and AUC of ticagrelor treatment schedules. C of AR-C124910XX values max 0-∞ max were comparable for the two hemodialysis treatments (Table displayed minor variability between the two hemodialysis 1). The variability (CV%) for both C and AUC of ticag- regimens (pre-hemodialysis, 54%; post-hemodialysis, 38%). max 0-∞ relor was approximately 50% in hemodialysis subjects, com- The variability of AUC of AR-C124910XX was approx- 0-∞ pared with 37% for C and 23% for AUC in healthy subjects. imately 40% for both hemodialysis treatment schedules. The max 0-∞ AR-C124910XX was rapidly formed, with a median t variability of C and AUC of AR-C124910XX was 60 max max 0-∞ of 2 h in both hemodialysis and healthy subjects, and the and 33%, respectively, for healthy subjects. The variability mean t was similar for all treatments (Table 1). In addi- of C and AUC of AR-C124910XX was considered to 1/2 max 0-∞ tion, the mean C of AR-C124910XX was 36% higher be generally similar for hemodialysis versus healthy max following the pre-hemodialysis regimen, compared with that subjects. in healthy subjects (Table 1, Table S1). The mean C of The mean metabolite-to-parent ratios for C (range, max max AR-C124910XX in patients receiving post-hemodialysis 0.26–0.33) and AUC (range, 0.38–0.50) were also 0-∞ Table 1 Pharmacokinetic (PK) PK parameter Pre-HD (n = 13) Post-HD (n = 12) Healthy subjects (n =13) parameters for ticagrelor and ARC-124910XX in hemodialysis Ticagrelor and healthy subjects C , ng/mL 598.4 (47.9) 560.3 (54.0) 370.8 (37.3) max AUC , ng·h/mL 3256.1 (52.5) 3015.1 (54.2) 2188.8 (22.6) 0-∞ t , h 2.0 (1.0–4.0) 2.0 (1.0–4.0) 2.0 (1.0–6.0) max t , h 8.4 (24.8) 8.2 (16.2) 8.3 (14.9) 1/2 AR-C124910XX C , ng/mL 152.3 (54.3) 130.8 (38.3) 111.7 (60.0) max AUC , ng·h/mL 1144.2 (36.2) 1127.8 (39.3) 1000.4 (33.2) 0-∞ t , h 2.0 (2.0–4.0) 2.0 (2.0–4.0) 2.0 (2.0–6.0) max t , h 7.4 (24.8) 7.3 (28.2) 8.4 (22.3) 1/2 AUC , area under the concentration curve (AUC) from time zero to infinity; C , maximum observed plasma 0-∞ max concentration; HD, hemodialysis; t , terminal elimination half-life; t , time to reach maximum plasma 1/2 max concentration Values are geometric mean (percentage coefficient of variation) for C ,AUC ; median (range) for t ; max 0-∞ max arithmetic mean (standard deviation) for t 1/2 Eur J Clin Pharmacol generally similar between hemodialysis and healthy subjects, approximately 2 h post-dose for all three treatments (Fig. 4). suggesting that the presence of ESRD requiring hemodialysis The PRU responses (both absolute values and changes from and the timing of hemodialysis have little influence on the the baseline) were similar following ticagrelor pre- and post- metabolic conversion of ticagrelor to AR-C124910XX. hemodialysis, while there were much greater responses (lower absolute PRU values) observed in the healthy subjects com- pared with the hemodialysis subjects (Table 2). The PRU dif- Pharmacodynamics ferences at baseline between hemodialysis subjects and healthy subjects contributed to the PRU difference observed The mean IPA time curves over 24 h post-dose were almost at early time points after ticagrelor dosing. Additionally, the indistinguishable for all three treatments (Fig. 2). Moreover, difference in effect of ticagrelor on PRU measured as the final extent IPA was over 90% for all three treatments approx- absolute PRU changes from their baselines is less pronounced imately2hafter ticagrelor administration(Fig. 2). The mean which indicates that hemodialysis subjects did not have a IPA and the AUEC were generally similar for all greater PRU response when compared with healthy subjects. max 0–48, IPA three treatments (Table 2), indicating that the presence of ESRD on hemodialysis and the timing of hemodialysis have Safety little influence on the effect of ticagrelor on IPA. The median time to IPA was longer when ticagrelor was administered AEs were reported in seven individuals during the study treat- max just prior to hemodialysis (4 h) than 1 day after hemodialysis ment period, distributed across all three treatments (five he- (2 h) or in healthy subjects (2 h) (Table 2). Time to IPA modialysis subjects [three when ticagrelor was administered max displayed much greater variability in hemodialysis subjects pre-hemodialysis and two when ticagrelor was administered (range 2–12 h for both treatments) than in healthy subjects post-hemodialysis] and two healthy subjects). There were no (2 h in all 13 subjects) (Table 2). The E model parameters reports of bleeding or dyspnea in hemodialysis or healthy max describing the PK/PD relationship between plasma concentra- subjects who received ticagrelor. One subject who received tions of ticagrelor and IPA were comparable across all three ticagrelor post-hemodialysis reported potentially treatment- treatments (Fig. 3), suggesting that the relationship between related AEs according to the investigator, comprising dizzi- ticagrelor concentrations and IPA is not altered in ESRD pa- ness, bronchospasm, and nausea. This patient withdrew from tients on hemodialysis (Table 2). the study before receiving the second ticagrelor dose. One The mean PRU was decreased following ticagrelor dosing, other hemodialysis subject withdrew from the study because with the greatest change from baseline occurring of a serious AE (thoracic vertebral fracture), which was not considered treatment related. There were no other serious AEs or deaths, and no clinically significant changes in laboratory parameters or vital signs were reported during the study. Discussion This study investigated the PK, PD, and safety of ticagrelor in subjects with ESRD on hemodialysis and compared the results with those from healthy subjects with normal renal function. The effects of timing of hemodialysis on the PK of ticagrelor were also investigated as part of the study. Overall, hemodialysis did not have a clinically significant impact on the exposure to ticagrelor or its active metabolite. The mean C and AUC of ticagrelor were 61 and 51%, max 0-∞ and 49 and 38% higher in pre- and post-hemodialysis subjects than in healthy subjects, respectively, while the mean C max and AUC of AR-C124910XX were 36 and 17%, and 14 0-∞ and 13% higher in pre- and post-hemodialysis subjects, re- spectively, than that in healthy subjects. Notably, the mean C and AUC of ticagrelor and AR-C124910XX were max 0-∞ generally similar following a single 90-mg dose of ticagrelor Fig. 2 Mean (SD) inhibition of platelet aggregation (IPA) time curves for 1 day after hemodialysis and 2 days prior to the next dialysis ticagrelor in hemodialysis and healthy subjects. HD hemodialysis, SD standard deviation treatment, indicating that timing of hemodialysis has little Eur J Clin Pharmacol Table 2 Pharmacodynamic (PD) PD parameter Pre-HD (n = 13) Post-HD (n = 12) Healthy subjects (n =13) parameters for ticagrelor in hemodialysis and healthy subjects IPA , % 92.8 (9.3) 95.5 (7.6) 95.9 (5.3) max TIPA , h 4.0 (2.0–12.0) 2.0 (2.0–12.0) 2.0 (2.0–2.0) max AUEC , %·h 2576.4 (32.1) 2550.3 (27.3) 2472.4 (46.0) 0–48, IPA E , % 92.1 (4.3) 105.3 (10.4) 101.3 (10.4) max EC , ng/mL 9.0 (1.4) 15.5 (6.4) 8.4 (3.4) Gamma 1.1 (0.2) 0.7 (0.1) 0.7 (0.2) PRU , PRU 83.8 (115.3) 33.4 (265.3) 7.3 (170.9) min TPRU , h 2.0 (2.0–12.0) 2.0 (2.0–4.0) 2.0 (2.0–6.0) min AUEC , PRU·h 12,440.0 (26.2) 12,577.2 (30.5) 7144.9 (42.9) 0–48, PRU AUEC area under the effect curve 0 to 48 h inhibition of platelet aggregation; AUEC area under 0–48, IPA, 0–48, PRU, the effect curve 0 to 48 h P2Y reaction units; EC , concentration that produces 50% maximum effect; E , 12 50 max maximum effect; Gamma, sigmoidicity or shape factor; HD, hemodialysis; IPA , maximum inhibition of max platelet aggregation; PRU , minimum P2Y reaction units; TIPA ,timeto IPA ; TPRU ,time toPRU min 12 max max min min Values are geometric mean (percentage coefficient of variation) for IPA , AUEC , PRU , and max 0–48, IPA min AUEC ; median (range) for TIPA and TPRU ; estimate (standard error) for E ,EC , and gamma 0–48, PRU max min max 50 effect on exposure to the drug or its metabolite. Moreover, the were almost indistinguishable, and final extent IPAwas > 90% mean metabolite-to-parent C and AUC ratios were com- at 2 h post-dose in both hemodialysis and healthy subjects. max 0-∞ parable following all three treatments, suggesting that hemo- Likewise, mean IPA and AUEC were similar across max 0–48, IPA dialysis has little impact on the metabolic conversion of the three treatments. Median time to IPA was slightly lon- max ticagrelor to AR-C124910XX. ger when ticagrelor was administered just prior to hemodial- The minimal impact of hemodialysis on ticagrelor PK ob- ysis versus 1 day after hemodialysis or in healthy subjects. served in this study is consistent with the known elimination However, time to IPA values in hemodialysis subjects max pathway of ticagrelor, which is predominantly via hepatic me- displayed greater variability than those for healthy subjects, tabolism of ticagrelor to AR-C1249XX, followed by biliary possibly reflecting the small sample size. Nevertheless, the secretion [5, 6]. Renal excretion plays only a minor role in the E model parameters describing the PK/PD relationship be- max elimination of ticagrelor [5]. Moreover, as ticagrelor is highly tween ticagrelor concentrations and IPA response were com- protein bound (> 99.8%) [15], dialysis is unlikely to have an parable across all three treatments. Of particular note, these appreciable impact on its plasma concentration. The results of findings show that hemodialysis subjects did not have greater this study are also consistent with findings from subjects with responses to ticagrelor than healthy subjects, and that the severe renal impairment not on hemodialysis, which demon- timing of hemodialysis has little influence on the PD effect strated exposure to ticagrelor and AR-C124910XX (20% low- of ticagrelor on IPA. er and 17% higher, respectively, vs healthy subjects) to be For all three treatments, reductions in PRU were observed largely unaffected by renal impairment [7]. following ticagrelor dosing, with the greatest reductions ob- IPA responses were also similar between hemodialysis and served at 2 h post-dose. The mean AUEC was of 0–48, PRU healthy subjects. Mean IPA time curves for all three treatments similar magnitude when ticagrelor was administered pre- or Fig. 3 Inhibition of platelet aggregation (IPA) concentration curves for ticagrelor in hemodialysis and healthy subjects. HD hemodialysis Eur J Clin Pharmacol Administration-approved label for ticagrelor, which suggests that even a twofold increase in exposure to ticagrelor does not warrant a dose adjustment [17]. Furthermore, the timing of hemodialysis has little effect on the PK and PD of ticagrelor. Contributions of Authors R. Teng was involved in developing the study concept and design, interpreting the data, and developing the man- uscript. S. Muldowney contributed to the study concept and design, in- terpretation of data, and development of the manuscript. Y. Zhao was involved in developing the study concept and design, interpreting the data, and developing the manuscript. J.K. Berg was involved in develop- ing the study concept and design, performing study research, interpreting the data, and developing the manuscript. J. Lu contributed to the study concept and design, interpretation of the data, and development of the manuscript. N.D. Khan was involved in developing the study concept and design, interpreting the data, and developing the manuscript. Funding This study was funded by AstraZeneca. Compliance with ethical standards Conflict of interest S. Muldowney and N.D. Khan are employees and shareholders of AstraZeneca. Y. Zhao is a former consultant to Fig. 4 Mean (SD) P2Y reaction unit (PRU) time curves for ticagrelor in 12 AstraZeneca. R. Teng and J. Lu are former employees of AstraZeneca. hemodialysis and healthy subjects. HD hemodialysis, SD standard J. Berg is an employee of DaVita Clinical Research and a principal in- deviation vestigator in the trial. Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institu- post-hemodialysis. However, there appeared to be a greater tional and/or national research committee and with the 1964 Helsinki reduction in PRU in healthy subjects. This finding may be at declaration and its later amendments or comparable ethical standards. least partially explained by baseline differences in PRU in hemodialysis versus healthy subjects that may have contribut- Informed consent Informed consent was obtained from all individual ed to the PRU difference observed at early time points after participants included in the study. ticagrelor dosing. Importantly, from a safety perspective in Open Access This article is distributed under the terms of the Creative this special population, this study highlights that hemodialysis Commons Attribution 4.0 International License (http:// subjects showed no greater PRU response, compared with creativecommons.org/licenses/by/4.0/), which permits unrestricted use, healthy subjects. distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link In this single-dose study, safety data were in line with pre- to the Creative Commons license, and indicate if changes were made. vious studies of ticagrelor in healthy volunteers [16] and sub- jects with severe renal impairment not on dialysis [7]. AEs were reported in seven subjects across all treatment regi- References mens—three subjects receiving ticagrelor pre-hemodialysis, two subjects receiving ticagrelor post-hemodialysis, and two 1. Nawarskas JJ, Snowden SS (2011) Critical appraisal of ticagrelor in healthy subjects. Similarly, vital signs and laboratory findings the management of acute coronary syndrome. Ther Clin Risk following ticagrelor administration were unremarkable in he- Manag 7:473–488 modialysis and healthy subjects, again consistent with previ- 2. O’Gara PT, Kushner FG, Ascheim DD et al (2013) 2013 ACCF/ ously reported findings in healthy [16] and renally impaired AHA guideline for the management of ST-elevation myocardial subjects [7]. infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice In conclusion, the slightly higher exposure to ticagrelor and Guidelines. J Am Coll Cardiol 61:e78–e140 its active metabolite in hemodialysis subjects, compared with 3. Steg PG, James SK, Atar D et al (2012) ESC guidelines for the healthy subjects, is considered of minimal clinical relevance. management of acute myocardial infarction in patients presenting Hemodialysis subjects had similar IPA response and no great- with ST-segment elevation. Eur Heart J 33:2569–2619 er PRU response versus healthy subjects, and the safety profile 4. Roffi M, Patrono C, Collet JP et al (2016) 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting was similar in both cohorts. Based on the PK, PD, and safety without persistent ST-segment elevation: task Force for the findings of this study, no ticagrelor dose adjustment is re- Management of Acute Coronary Syndromes in Patients quired for patients with ESRD on hemodialysis. These find- Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 37:267–315 ings are consistent with the US Food and Drug Eur J Clin Pharmacol 5. Teng R, Oliver S, Hayes MA, Butler K (2010) Absorption, distri- update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 80:572–586 bution, metabolism, and excretion of ticagrelor in healthy subjects. Drug Metab Dispos 38:1514–1521 12. Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance 6. Teng R (2015) Ticagrelor: pharmacokinetic, pharmacodynamic from serum creatinine. Nephron 16:31–41 and pharmacogenetic profile: an update. Clin Pharmacokinet 13. Sillen H, Cook M, Davis P (2010) Determination of ticagrelor and 54:1125–1138 two metabolites in plasma samples by liquid chromatography and 7. Butler K, Teng R (2012) Pharmacokinetics, pharmacodynamics, mass spectrometry. J Chromatogr B Analyt Technol Biomed Life and safety of ticagrelor in volunteers with severe renal impairment. Sci 878:2299–2306 J Clin Pharmacol 52:1388–1398 14. Butler K, Teng R (2010) Pharmacokinetics, pharmacodynamics, 8. Wang H, Qi J, Li Y et al (2017) Pharmacodynamics and pharma- safety and tolerability of multiple ascending doses of ticagrelor in cokinetics of ticagrelor vs. clopidogrel in patients with acute coro- healthy volunteers. Br J Clin Pharmacol 70:65–77 nary syndromes and chronic kidney disease. Br J Clin Pharmacol 15. Butler K, Teng R (2011) Pharmacokinetics, pharmacodynamics, 84:88–96 and safety of ticagrelor in volunteers with mild hepatic impairment. 9. USRDS United States Renal Data System (2016) USRDS Annual J Clin Pharmacol 51:978–987 Data Report|Volume 2 ESRD in the United States. Chapter 9: 16. Teng R, Butler K (2010) Pharmacokinetics, pharmacodynamics, Cardiovascular disease in patients with ESRD. 2.9:465–480 tolerability and safety of single ascending doses of ticagrelor, a 10. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY (2004) reversibly binding oral P2Y(12) receptor antagonist, in healthy sub- Chronic kidney disease and the risks of death, cardiovascular jects. Eur J Clin Pharmacol 66:487–496 events, and hospitalization. N Engl J Med 351:1296–1305 17. AstraZeneca (2016) BRILINTA highlights of prescribing informa- 11. Herzog CA, Asinger RW, Berger AK et al (2011) tion. BRILINTA (ticagrelor) tablets for oral use:1-10, available at: Cardiovascular disease in chronic kidney disease. A clinical https://www.azpicentral.com/brilinta/brilinta.pdf

Journal

European Journal of Clinical PharmacologySpringer Journals

Published: May 30, 2018

References

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